Cancer therapies aim to exploit differences between cancer cells and normal cells to obtain a therapeutic window wherein the treatment is toxic to the cancer but not the organism. Since cancers are the consequence of somatic genetic alterations that collectively lead to tumor formation and growth, a dominant therapeutic paradigm is to target these altered genes and their pathways.1 These underlying principles fueled the cancer genomic revolution leading to the discovery of many of the genes (and genotypes) that initiate and drive cancer growth. Unfortunately, these genes seldom affect proteins that can readily be chemically manipulated, leaving a long list of putative targets but little guidance as to which to “drug”. In order to fulfill the promise of targeted therapy, we now need to match these cancer genotypes with new chemical sensitivities.
Lung cancer remains the leading cause of cancer related death in the United States and there is an urgent need for new and effective therapy. Lung adenocarcinomas, the most common histologic type, originate from somatic alterations in different genes that drive tumor growth including the tyrosine kinases, EGFR and ALK. Mutations in EGFR or structural rearrangements of ALK lead to constitutive tyrosine kinase activity that these cancers depend on to grow. As such, patients whose tumors harbor these alterations exhibit dramatic clinical responses to their respective inhibitors, erlotinib and crizotinib.2,3 Unfortunately, EGFR mutations and ALK alterations occur in the minority of patients, and most patients still lack a comparably efficacious targeted therapy. Hence, a first step toward new therapies has been to characterize cancer genomes in order to identify genetic alterations that can be similarly targeted.
Large-scale efforts to characterize the cancer genome in lung adenocarcinoma, however, have not revealed common alterations that can be readily “drugged”. The most frequent alterations discovered in whole genome sequence analysis of 200 lung adenocarcinomas were in already known driver genes including TP53, KRAS, EGFR, and ALK.4,5 Newly discovered alterations were the exception and, unlike EGFR or ALK, offer no clear path for developing small molecule modulators. Likewise, genome-wide copy number analyses across hundreds of lung adenocarcinomas have identified putative targets, but again without any known corresponding chemical dependency.6 
Thus, a need exists for new chemical identities that selectively target specific anomalies (e.g., genetic, epigenetic and/or metabolic) in select cancer patient sub-population, thereby permitting the development of personalized medicine in cancer therapy. An important consideration in the development of such therapeutic agents is their relative toxicity towards normal human tissue and the cancerous tissue or cells. This therapeutic index defines the dose at which treatments can be administered and their effectiveness. In this context, identification of novel approaches to target cancerous tissue while sparing normal tissue remains an important objective.